Semaglutide may improve NYHA functional class in obesity-related HFpEF

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) treated with semaglutide are more likely to show an improvement in NYHA functional class at 52 weeks than those who received placebo, according to a study.

“Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight and biomarkers of inflammation and congestion in all NYHA functional class categories,” the investigators said. Additionally, “[s]emaglutide-mediated improvements in health status were especially large in patients with NYHA functional classes III/IV.”

A prespecified analysis was carried out using pooled data from two international, double-blind, randomized trials (ie, STEP-HFpEF and STEP-HFpEF type 2 diabetes). These studies collectively randomized a total of 1,145 participants with obesity-related HFpEF to receive either once-weekly semaglutide 2.4 mg or placebo for 52 weeks.

The investigators assessed the change in NYHA functional class from baseline to week 52 and examined the effects of the study drug on the dual primary, confirmatory secondary, and selected exploratory endpoints according to baseline NYHA functional class.

At 52 weeks, the semaglutide group showed a higher rate of improvement in NYHA functional class (32.6 percent vs 21.5 percent; odds ratio [OR], 1.62, 95 percent confidence interval [CI], 1.62‒2.99; p<0.001) and a lower incidence of deterioration in NYHA functional class (2.09 percent vs 5.24 percent; OR, 0.36, 95 percent CI, 0.19‒0.70; p=0.003) relative to the placebo group. [J Am Coll Cardiol 2024;84:247-257]

Semaglutide also led to improvements in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) across NYHA functional class categories, particularly in classes III/IV (10.5 points, 95 percent CI, 6.6‒14.4) vs class II (6.0 points, 95 percent CI, 3.4‒8.6; p=0.06 for interaction).

Semaglutide-treated patients also had consistent improvements in 6-minute walking distance (6MWD) and the hierarchical composite endpoint (ie, death, HF events, differences in KCCQ-CSS, and 6MWD changes), as well as reductions in C-reactive protein (CRP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) across NYHA functional class categories (p=NS).

However, body weight reduction did not differ significantly between the semaglutide and the placebo groups regardless of baseline NYHA functional class category (class II: ‒8.4 percent, 95 percent CI, ‒9.4 to ‒7.3; classes III/IV: ‒8.3 percent, 95 percent CI, ‒9.9 to ‒6.8; p=0.96 for interaction).

Mechanisms

Several factors appear to drive the improvement in NYHA functional class in the STEP-HFpEF program. [Arterioscler Thromb Vasc Biol 2020;40:506-522]

“Weight loss itself can result in improved functional status, but our data suggest that weight-independent effects of semaglutide also contribute to the observed benefits,” the investigators said.

“Specifically, there appeared to be a larger improvement in HF-related symptoms and physical limitations among patients in NYHA functional classes III/IV than those in NYHA functional class II, even though the degree of weight loss was similar across NYHA subgroups,” they added.

Moreover, the decrease in NT-proBNP with semaglutide irrespective of NYHA functional class indicates a favourable effect on the pathobiology of obesity-related HFpEF across the spectrum of functional limitations, while a reduction in CRP suggests an anti-inflammatory mechanism, according to the investigators.

With regard to safety, semaglutide was well tolerated regardless of functional limitations at baseline, with infrequent cases of serious adverse events relative to placebo.